Based on the presence of islet cell autoantibodies and a strong HLA linkage, type 1 diabetes is regarded as a chronic autoimmune disease that can be predicted. Many issues remain unresolved and the objective of the present competing continuation program project of actively collaborating experts in type 1 diabetes research is to determine the mechanisms of type 1 diabetes development in individuals who shares the underlying markers of disease risk but differ in phenotypes and non-HLA genetic factors. Our program project brings together experts on cellular and humoral immunology in type 1 diabetes with human genome and molecular biotechnology expertise in genome wide analysis of genes that contribute to type 1 diabetes risk and in DNA sequencing of high throughput. A coordinated multidisciplinary approach to study individuals at risk for type 1 diabetes as well as different type 1 diabetes phenotypes are taken to dissect the mechanism by which type 1 diabetes develop. Studies of subjects at type 1 diabetes risk who are followed from birth or in first degree relatives, the general population as well as in slow onset type 1.5 diabetes patients will determine what makes an individual develop clinical type 1 diabetes. The following individual projects interact in this program project: Project 1 will measure variation in T cell activation thresholds during progression to autoimmune diabetes and identify mechanisms involved in the generation of TCR avidity spectrum for recognition of autoantigens (Gerald T. Nepom); Project 2 will determine the mechanisms by which conformation-dependent autoantibodies are generated and associated with type 1 diabetes risk and the role of enhanced autoantigen presentation by autoantibodies (?ke Lernmark); Project 3 will investigate whether the progression of type 1.5 diabetes compared to type 1 diabetes is characterized by increased regulation of islet specific T cell responses, a decrease in effector T cell populations, or both (Jerry Palmer); and Project 4 will test in the general population whether individuals with elevated genetic risk outside HLA-DQ develop type 1 diabetes autoantibody markers and type 1 diabetes more often than those without such risk. Core B will provide expertise and a state of the art facility for large scale, high resolution genetic mapping, DNA sequencing and protein sequencing projects. Project 1 will collaborate with Project 2 and 3 specifically on the generation of T cell clones with defined autoantigen epitope and HLA restriction. Both Project 1 and 2 will study subjects in collaboration with Projects 3 and 4. The interaction between Projects 3 and 4 will provide a critical span of type 1 diabetes related phenotypes combining subjects with both rapid and slow progression to type 1 diabetes. Our program project has generated more than 70 publications and will continue to dissect genetic and immunological factors which control progression to clinical type 1 diabetes. The long term objective is to identify novel approaches to prevention and cure of type 1 diabetes.